What is IC/BPS?
Interstitial Cystitis/Bladder Pain Syndrome - shortly called IC/BPS - is a chronic, long lasting condition that causes painful urinary symptoms which significantly affect the patients' quality of life. As IC/BPS progresses, the pain and the frequent voiding can severely impede work, sexual intercourse, social life and night-time resting.
According to our present knowledge, there is no definitive cure for IC/BPS. On the other hand, patients can be symptom-free for years, and the normal quality of life can be preserved assuming they get the appropriate treatment. The maintenance therapy should include monitoring the patient's status for years, possibly lifelong.
Currently, even in the countries of most advanced healthcare, only 5-10% of the IC/BPS patients are diagnosed, although it is estimated that about 2.4% of the population are affected. Unfortunately, the later a patient is being diagnosed, the more severe the symptoms of IC/BPS are.
Urosystem's mission is to provide an all-round solution for IC/BPS patients - from the diagnosis to the proper treatment of multiple levels.
According to the definition of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, the USA) Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic, or long-lasting, condition that causes painful urinary symptoms. Its symptoms significantly affect the patient's quality of life. As IC/BPS progresses, the pain and the frequent voiding (which may exceed more than 80 occasions per day) can severely impede work, sexual intercourse, social life and night-time resting. Other chronic conditions occur more frequently in IC/BPS patients than in the general population.
According to our present knowledge, there is no permanent cure for IC/BPS.  On the other hand, patients can get free from symptoms for years, and their standard quality of life can be preserved, assuming they get the appropriate treatment. Due to the increasing number of diagnosed cases and the length of therapy, IC/BPS shall demand a growing amount of resources from the healthcare systems in the near future.
The Known Facts
The causes of IC/BPS are still not known. The possible explanations are the dysfunction of the related nerves, autoimmune problems, allergic reactions, and stress. Hereditary factors may take part, too. Nevertheless, none of these hypotheses have been proven scientifically.
The condition itself, on the other hand, has been well described. The symptoms occur because of the inadequate status of the mucosa of the bladder and the upper part of the urethra. The healthy superficial mucus layer of the mucosa – which consists of glucose-amino-glycan or GAG – prevents salts, acids and other metabolic products (being present in the urine naturally) getting into the deeper layers of the bladder wall, and irritating the sub-mucosal pain receptors. In IC/BPS, this GAG-layer is damaged and enables the compounds described above to reach the receptors. This results in a sterile inflammation – in which there is no bacteria present – which can spread to the deeper layers of the bladder wall, too, and leads to an increased amount of mast cells. These cells produce histamine, which increases the pain. The constant irritation raises the number of pain receptors, which makes the symptoms worse. If the inflammation persists for years, other elements of the connective tissues build up in the edematous tissue, which makes the bladder wall lose its elastic properties. At the end of this process, an end-stage bladder can develop (a rigid bladder with very low capacity), which is an irreversible condition. The thick and rigid bladder wall slowly compresses the ureters, and as a consequence, kidney failure may appear.
Since the cause of the GAG-layer loss is not known, it is impossible to prevent IC/BPS. Moreover, there is no therapy available which cures the condition for good. The early diagnosis and the proper treatment can stop the progression of IC/BPS.
Diagnosis and Prevalence:
Despite many efforts taken to find any marker, so far nothing has been discovered that can be inarguably associated with IC/BPS. There are no alterations either that would refer to IC/BPS, without doubt, so using the most known imaging methods in themselves do not provide a precise diagnosis. The image of the healthy bladder and the disrupted one may be identical. On the other hand, the insufficiency of the GAG-layer can refer to other diseases, too. Excluding malignant processes and infections is necessary, but even the presence of any other condition cannot rule out IC/BPS. Therefore, IC/BPS can sometimes only be diagnosed after the successful treatment of the easily identifiable, coincident condition.
The Typical Symptoms of IC/BPS
The usual symptoms of IC/BPS can be divided into two major groups.
Not only the urethra and the bladder can be affected, but also the lower abdomen, the pelvic or perineal area (moreover, in women the vagina, in men the scrotum and the penis)
Its intensity may correlate with the filling of the bladder, whereas voiding may temporarily reduce it
Assuming the urethra is affected, sexual intercourse may be painful
Its level varies from mild discomfort to severe, excruciating pain
In the beginning, the sparse and short painful periods are separated with long, symptomless intervals. As IC/BPS progresses, pain becomes permanent, and it can occur without any correlation to voiding
Even during long lasting symptom-free, stable condition, patients may experience flare-ups from time to time.
In the beginning, the frequency is slightly higher than normal. In severe cases 60–80 urination a day is possible, too
Sudden urgency may occur, followed by spasms and pain
In mild cases, the abnormal frequency of voiding shows up only in daytime. With progression nocturia develops, the need for voiding can occur several times at night.
The voided volume (the urine portion) is very small and correlates to the amount of liquid consumed.
In severe cases, the need for voiding persists after urinating too.
The presence of these symptoms varies by patients and is affected by several factors. Namely, consuming certain foods and drinks, the amount of physical and/or mental stress, digestive disorders, urinary infections (UTIs) and (in women) their menstrual cycle (the symptoms are usually worse after ovulation).
Diagnosing IC/BPS – Then and Now
Most urologists define a condition as IC/BPS if the characteristic symptoms persist for a certain period (1.5–6 months) given that every disease of similar symptoms can be excluded. Filling out questionnaires can identify the presence of symptoms; the O’Leary-Sant Symptom Index is one of the most frequently used ones. However, because no lab tests or any other kind of examination can unequivocally confirm IC/BPS, the condition can never be diagnosed with a 100% certainty. Fortunately, not only are there a handful of supplemental examinations that can be used for refining the diagnosis, but also the medical practice has improved significantly in this field in recent years.
The most important tool for diagnosing IC/BPS used to be the Potassium Sensitivity Test (aka. Parsons-test or PST). This confirmed the insufficiency of the GAG-layer by the pain generated by potassium-chloride instilled into the bladder. (In case of a healthy GAG-layer there is no significant pain observed). This tool, however, was not only unnecessarily invasive but unpleasant, too, given that the patients had severe pain due to the solution itself. The Parsons-test did not provide information for a quantitative analysis either. In a later version of this sensitivity test (modified Parsons test) the bladder was filled with diluted potassium-chloride solution to determine its maximum capacity, and then the same process was repeated with physiological salt solution. The proportion of the two values referred to the sensitivity of the bladder wall for the concentration of the urine. Although the modified Parsons test could be used for quantitative measurements as well, it was just as invasive, time-consuming, and its accuracy was not higher than that of the original version. Due to these issues, neither tests are recommended in the recent guidelines. 
The lidocaine test works oppositely. This substance is to moderate bladder pain, so given that the source of the pain is the bladder itself, the instilled lidocaine lessen the symptoms in case of IC/BPS. This tool is definitely more comfortable than the potassium sensitivity test, but it is just as invasive and does not enable quantitative analyses either.
A new diagnostic tool is the GAG-layer Integrity Test, which uses a two days' voiding diary, and it is non-invasive and painless too. This test is based on the fact that for observing the correlation between the urine concentration and the bladder capacity, nothing need be instilled; the solution of dissolved salts is already present – in the form of urine itself. The concentration of urine substances – salts included – depends on the amount of consumed liquid. The volume of each voiding can be measured for a day on which the patient consumes the least liquid they can, then the same thing can be done on the second day on which the patient consumes as much liquid as they can. In case of a healthy bladder wall, there is no correlation between the mean voided volumes and the liquid intake. In the early phase of IC/BPS, the higher liquid consumption results in 30–50% higher urine portions. As the disease progresses, the difference increases to 50–100%; in severe cases, it can be 300–500%. Therefore, not only does the 2-day Voiding Diary indicate the damaged bladder wall, but also it describes the amount of damage, numerically. Thus, the GAG-layer Integrity Test enables quantitative analysis, too.
The correlation between the mean of the daytime urine portion and the total amount of daytime urine, in case of healthy people and IC/BPS patients (see figure).
There are certain diseases which occur significantly more likely together with IC/BPS; their presence may support the diagnosis. This group consists of allergic symptoms, migraine, irritable bowel syndrome, endometriosis, vulvodynia, chronic fatigue syndrome, Sjögren-syndrome, panic disorder, and many more conditions. 
Low-pressure cystoscopy is recommended if there is blood in the urine, or urine cytology refers to the chance of a malignant process (or there is an unambiguously positive result), or the patient's condition becomes worse despite the combined therapy they get, to examine whether bladder cancer or another disease of similar symptoms are present. The biopsy of the bladder mucosa is performed only if the cystoscopic image reveals areas that may refer to malignancy. If cystoscopy does not raise suspicion of malignancy, urine cytology should be performed, which is the most sensitive non-invasive method.
Recording the patient's anamnesis provide useful information, too. This should include not only the current symptoms but also the history of their earlier infections, other diseases they suffer in (mainly focusing on autoimmune diseases and digestive disorders), medicines and/or antibiotics being taken or were taken before, the patients' diet and other lifestyle characteristics and the correlation between the symptoms and any of the information described above.
How Many IC/BPS Patients are there?
The occurrence of disease can usually be described by two kinds of data. Incidence means the newly registered cases during a certain period (usually a year). Prevalence, on the other hand, means the total amount of people affected by the disease at a certain point of time. In the case of IC/BPS, which appears to be a life-long condition, the latter data is relevant.
The international estimations of prevalence are based on the presence of symptoms, filling in questionnaires, and data on patients having been diagnosed with IC/BPS. The number of people affected by IC/BPS is usually referred to as 100,000 people.
However, neither the questionnaires nor the way of their evaluation is standardized. Certain studies that used only the data gathered from doctors focusing on the diagnosed IC/BPS cases concluded a prevalence of 45–197/100,000. On the other hand, a survey in which households had been contacted by phone estimated 1,900–4,200/100,000 men and 2,750–6350/100,000 women affected by IC/BPS. A mere 10% of the latter group had been diagnosed.   According to another research based on self-reporting via e-mail, IC/BPS can affect 258–13,114/100,000 people, depending on the way of calculations.
In 2017 Interstitial Cystitis Association (ICA) reported that alone in the USA, there are 3–8 million women and 1–4 million men affected by IC/BPS. In recent years, this estimation seems to have been accepted by many relevant papers and organizations. ,  Considering the mean of both values, a prevalence of 2,400/100,000 appears to be a reasonable calculation.
The mean age of patients appears to be 40 years, but IC/BPS can show up at younger or older age, too.
That said, the diagnosis rate of IC/BPS is less than 5–10%, even in the countries with the most advanced healthcare. There is no other disorder of this seriousness, which has a lower diagnostic rate.
The Treatment of IC/BPS
Most guidelines – including the one of American Urological Association (AUA) – shares the view that the doctor should start with the least invasive method and progress step by step towards the more invasive technics.
Lifestyle Changes and Diet
The least invasive therapeutic possibilities describe lifestyle changes. Diet has a major impact on the symptoms. IC/BPS food and drink lists are widely available on the internet , , , and scientific papers have been published about this topic, too, . Most of the references agree that certain nourishments irritate the damaged bladder wall. Lists usually mention the following things:
Hot and spicy foods
Sour and acidic foods, including carbonated drinks
Some fruit of high acid content
Tea or certain dietary supplements containing fragrance oil and/or volatile oil compounds
Indeed, following an IC/BPS-friendly diet can help mitigate the symptoms. However, lifestyle and diet changes alone do not always work, especially in severe cases. It usually takes a considerable amount of time until the effects manifest, and during this sort of therapy, the symptoms may become worse.
If there is no improvement experienced, the next major line of treatment is oral therapy. The most common medicines usually contain one or more of the following active ingredients:
Gabapentin nerve pain relieve
It must be pointed out that the list of approved – and available – products greatly varies by country.
There have been plenty of studies examining the efficacy of these substances, it is summarized on many pages, too.  These agents have anti-inflammatory, pain mediator blocking and antidepressant effect; therefore, oral medication is an effective way of mitigating the urinary and/or the pain symptoms, thus improving the patient's quality of life.
Urine alkalization is an important part of the oral treatment, too, since the acidic urine can irritate the bladder and make the symptoms worse. Avoiding food groups that make the urine more acidic is not effective enough in many cases. Therefore, alkalizing pills (medicines or food supplements) play a major role in oral medication, as well.
These agents, however, have little to no effect on the integrity of the GAG-layer. It is worth mentioning there are certain products which do contain one or more active pharmaceutical ingredients (detailed later) used for GAG-layer replenishment. Many of them are widely known and available on the internet. In this group, the most important medicine is Pentosan Polysulfate Sodium (PPS, Elmiron, SP-54), which is approved by the Food and Drug Administration (FDA, the USA), and considered to be the only oral drug that actively helps GAG-layer replenishment.
Regardless of using GAG-layer replenishment agents, oral therapy has some considerable drawbacks. To reach the bladder the drugs must be absorbed in the digestive system, enter the circulation and reach other tissues too. This fact lowers the efficacy of the drugs and increases the chance of side effects. PPS, for example, has to be taken for 3 months or more to experience its effect on the GAG-layer. Orally administered PPS taken over longer period may have serious side-effects; a recent discovery on this topic is particularly concerning.
Local Treatment (Intravesical Instillation)
Local Treatment (Intravesical Instillation)
The next possibility is the local treatment, which means instilling certain substances directly into the bladder.
In the last 20 years there have been plenty of active agents tried out. Some of these, for example BCG (Bacillus Calmette-Guarin) have turned out to be ineffective. Others, like interfering with the nerve growth factors, have had safety issues. With certain substances, only partial improvement has been achieved: with vanilloids, for example, pain have had been reduced, but no improvement has been observed regarding the urinary symptoms. There are some agents which have been under examination right now, but either the results have been controversial and/or inconclusive so far, or there have not been enough clinical tests yet. Blocking the P2X3 receptors (which affect the bladder activity) might be promising, but further experiments would be needed. Botulinum toxin A (BTX-A, Botox) has been examined several times, but the results seem controversial.  Using liposomes for delivering different agents might be an efficient method , but, again, further experiments would be needed.
Regarding the active ingredients, there are six major compounds which that are associated with GAG-layer replenishment. These are the following:
Pentosan polysulphate sodium (PPS, Elmiron, SP-54)
Dimethyl sulfoxide (DMSO, Rimso-50)
Lidocaine (alkalized lidocaine, AL)
Hyaluronic acid (HA)
Chondroitin sulphate (CS)
The clinical data on these substances are, on the other hand, controversial.
The structure of PPS is similar to those compounds which are naturally present in the GAG-layer. Its mechanism of action is still not known, but it might be an effective intravesical medicine.
DMSO is the only drug that is approved by the FDA for bladder instillation. According to some papers, it is more effective than certain other agents , whereas other references point out the issues related to DMSO.
Alkalized lidocaine (AL) is often used in different bladder cocktails. According to certain sources, it is an effective medicine for GAG-layer replenishment on its own. Most therapists think it can raise the efficacy of other compounds, even if there are studies denying it.
Heparin, hyaluronic acid and chondroitin sulphate are natural components of the GAG-layer. Heparin, either alone or with other compounds is often used in the local treatment. There are data that says it is less effective than e.g. DMSO (see above). Hyaluronic acid may be the most widespread component; its efficacy has been examined several times, with different results. , , . The available data are similarly controversial for chondroitin sulphate, too. , , . According to some studies, HA+CS might be just as effective as DMSO.
In practice, different therapists use different bladder cocktails, hoping that the patient will respond to the treatment.
The large number of controversial data might be based on several facts. Firstly, the etiology of IC/BPS is still not known. If the disease can appear for different reasons, patients with different etiology might respond differently to the treatments. Secondly, in many countries only one or very few of these medicines are approved, which alone hinders the possibility of building an objective and comparative picture. Thirdly, in most countries there are only a few agents or cocktails used for instillation, usually in a magistral form, which makes it very hard to run clinical trials with ample sample sizes.
It is worth examining why local treatment is less popular to oral medication in spite of it is more effective – providing the right medicine is used. Invasiveness is an important factor. Many doctors tend to avoid using a catheter unless it is inevitable. Patients often refuse instillation therapy, being afraid of the pain, and the risk of further issues – microlesions and infections – a catheter can cause. To overcome these problems, Urosystem has developed UroDapter® and UroStill®. The former one is a small device which that replaces the catheter. The latter one is a device that enables self-instillation for female patients. With UroStill® the bladder treatment can be performed at home, without any direct assistance from the therapist.
It is inarguable that the first lines of the treatment – the less invasive methods, such as diet and oral medication – are necessary. Unfortunately, not only does the diagnosis take a long time, but also the effect of the less invasive therapies appears later. This leads to a common situation in which the patients waste 1–3 years or more living with hardly tolerable pain, severe urinary syndromes and a gradually worsening quality of life. The more time has been spent in this way, the more likely it is that the patient will not respond to the less invasive lines of treatment at all.
Our recommendations are summarized in the following flowchart. In cases of severe symptoms, it is recommended to start with combined therapy of oral and intravesical treatments so that the patient's condition can improve as soon as it can.
The flowchart of diagnosis and therapy of IC/BPS. By 100% of the GAG-layer integrity test, the mean of the urine portions measured on the first (low fluid intake) day should be meant (described in the Diagnosing IC/BPS chapter)
As it is shown, the applied line of treatment depends on the findings of the GAG-layer integrity test. Lifestyle changes, diet and oral medication is efficient and sufficient only in mild cases of IC/BPS. Patient follow-up is necessary in these cases, too, because despite the applied treatments a worsening condition cannot be ruled out. (The patient follow-up system has not been implemented to this website yet.)
At more severe conditions the GAG-layer replenishment via bladder instillations shall be started immediately, but all the less invasive methods are usually performed simultaneously.
More invasive therapies – including nerve stimulation, fulguration of the damaged regions of the GAG-layer or cystectomy – are performed only if all the other treatments have been ineffective. Alternative methods – including acupuncture, high-pressure oxygen therapy – are mostly recommended as supplementary treatments, taking into consideration their wrong cost-benefit ratio.